Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation

作者：Ferreira de Melo Thais Regina; Kumkhaek Chutima; dos Santos Fernandes Guilherme Felipe; Lopes Pires Maria Elisa; Chelucci Rafael Consolin; Barbieri Karina Pereira; Coelho Fernanda; de Oliveira Capote Ticiana Sidorenko; Lanaro Carolina; Carlos Iracilda Zeppone; Marcondes Sisi; Chegaev Konstantin; Guglielmo Stefano; Fruttero Roberta; Chung Man Chin; Costa Fernando Ferreira; Rodgers Griffin P; dos Santos Jean Leandro^*

来源：European Journal of Medicinal Chemistry, 2018, 154: 341-353.

DOI：10.1016/j.ejmech.2018.05.008

• Analgesic activity
• Antiplatelet activity
• Epigenetic
• Fetal hemoglobin
• Furoxan
• Sickle cell disease

N-oxide derivatives 5(a-b), 8(a-b), and 11(a-c) were designed, synthesized and evaluated in vitro and in vivo as potential drugs that are able to ameliorate sickle cell disease (SCD) symptoms. All of the compounds demonstrated the capacity to releasing nitric oxide at different levels ranging from 0.8 to 30.1%, in vivo analgesic activity and ability to reduce TNF-alpha, levels in the supernatants of monocyte cultures. The most active compound (8b) protected 50.1% against acetic acid-induced abdominal constrictions, while dipyrone, which was used as a control only protected 35%. Compounds 8a and 8b inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Both compounds increased gamma-globin in K562 cells at 100 mu M. The mechanisms involved in the gamma-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds. In vitro, the most promising compound (8b) was not cytotoxic, mutagenic and genotoxic.

• 出版日期2018-6-25